The primary factor leading to the onset of osteoporosis is age related bone loss; however, the potentially disastrous affects of bone loss may be minimized by increasing peak bone mass early in life. The proposed research evaluates relationships among muscle mass, bone mass, and physical activity in myostatin-deficient mice in order to better understand the mechanisms that increase bone strength during growth and maximize bone mass at adulthood. Myostatin (GDF-8) is a negative regulator of skeletal muscle growth and myostatin null mice show a doubling of muscle fiber size and number compared to normal mice. Recent studies have shown that myostatin inhibitors have the potential to slow and/or prevent the development of obesity, type 2 diabetes, and muscle wasting disorders such as muscular dystrophy and cachexia. Preliminary results presented in this application indicate that loss of myostatin function also significantly increases bone formation, bone density, and bone strength. Myostatin inhibitors may therefore serve as a novel treatment for the prevention of osteoporosis. The purpose of this study is to test the hypothesis that myostatin deficiency increases bone formation and bone strength during postnatal development by increasing muscle mass. This project seeks to define the mechanisms underlying the positive effects of myostatin deficiency on bone strength with the following Specific Aims: Specific Aim 1 will determine if increased muscle mass due to myostatin deficiency increases bone mineral density and bone strength independent of total body mass and fat mass. Specific Aim 2 will determine if myostatin deficiency increases bone formation through a mechanotransduction pathway. Specific Aim 3 examines the effects of myostatin deficiency and intense exercise on bone mass and strength. This research will critically evaluate the effectiveness of targeting muscle mass as a therapeutic strategy for improving bone health, and will in this way contribute significantly to the development of novel treatments for the prevention of osteoporosis.